Administration of some drugs, such as amino and nucleic acid analogs, peptides peptidomimetic drugs, various antibiotics, various anti-viral drugs, and some others, to a mammal, results in delivery to gastrointestinal tract and absorption of these drugs only in specific regions of the gastrointestinal tract, like the stomach, duodenum and small intestine, such that only drugs delivered to proximity of these regions are absorbed. This phenomenon is frequently referred to as “narrow absorption window” (NAW). Various other drugs' action sites are located in specific regions of the gastrointestinal tract. In addition, various other drugs, such as water-insoluble drugs, possess pharmaceutical rationales for gastric retentive administration. Moreover, the transit time through every region of gastrointestinal tract is a highly variable value.
Despite the advances in sustained release technology for many drugs, controlled release of drugs having a relatively narrow absorption window in the gastrointestinal tract remains a challenge. A need exists to extend the gastric residence time for these drugs, so that the drug is released into the proximity of its site of absorption (or action) for an extended period, or reaches other sites of the GI tract in a uniform manner. Examples of delivery systems capable of increasing the residence time of a drug are floating low-density dosage forms, such as so-called hydrodynamically-balanced delivery systems, effervescent systems comprising gas-generating materials Also other delivery systems, such as high-density dosage forms and bioadhesive or mucoadhesive formulations that slow upper GI transit by adhering to the intestinal mucosa have been attempted (Hwang, S J. et al., Critical Reviews in Therapeutic Drug Carrier Systems, 15 (3): 243-84 (1998); Desai, S. and Bolton, S., Pharmac. Res. 10 (9): 1321-25 (1993); Whitehead, L. et al., European J. Pharm. Sci., 4 (1): S182 (1996); Iannuccelli, V. et al., Intern. J. Pharmac. 174: 55-62 (1998); Jimenez-Castellanos, N R. et al., Drug Develop. Industr. Pharmacy 19: 143 (1993); Moës, A J. Crit. Rev. Ther. Drug Carrier Syst. 10(2): 143-195 (1993)).
Controlled-release (CR) drug formulations present the advantage of delivering the drug of interest over a prolonged time intervals and eliminating the inconvenience of repetitive daily dosages with concomitant side effects. However, conventional CR drug delivery systems are seldom suitable for drugs with a relatively narrow absorption window in the gastrointestinal tract, since their residence time in or above the absorption window is shorter than the release time span that could be deemed beneficial. Thus, there is a need in the art for controlled-release drug formulations that provide sustained release of drugs having a relatively narrow absorption window in the gastrointestinal tract. Similarly, it is deemed beneficial in certain instances to establish therapeutic blood levels quickly and sustain them over longer periods, the subject known in the art as “the loading dose”, and there is a need in the art for a combined drug formulation comprising an immediate release component and a sustained release component suitable for delivery of narrow-absorption window substances. U.S. Pat. No. 6,685,962 B2, incorporated herein by reference, provides pharmaceutical gastroretentive drug delivery systems for the controlled release of an active agent in the gastrointestinal tract.
The present invention satisfies the need in the art for formulations that provide sustained release or combined immediate release and sustained release of drugs with a narrow absorption window in the gastrointestinal tract, or other rationales for a gastroretentive administration, by providing gastroretentive drug formulations that are also completely biodegradable, and with a relatively high loading capacity.